Phase 2 Study of MP4CO to Treat Vaso-occlusive Sickle Crisis

NCT01925001 | Withdrawn Phase 2 DMC

• 1 other identifier: SCD-206
• Study Type: interventional
• Target: N/A
• Locations: 9 countries
• Sites: 14

Brief Summary

Sickle Cell disease is caused by an inherited hemoglobin disorder. Healthy red blood cells are discoid and can deform and move through small blood vessels to carry oxygen to all parts of the body. In Sickle Cell disease, as red blood cells circulate and oxygen is released, the deoxygenated abnormal Hemoglobin S can begin to polymerize and cause red cells to become sticky and elongated. These "sickled" red cells are less flexible and will obstruct small blood vessels and prevent normal red cells from circulating freely, which limits oxygen delivery to tissues and organs. This is known as a "sickling crisis" or "vaso-occlusive crisis" and is the leading cause of hospitalization in patients with Sickle Cell disease. Patients suffering from a sickle crisis experience severe pain and are at risk of stroke, heart attack or even death. Current therapy is limited to hydration and symptomatic pain relief. The administration of MP4CO as an adjunct treatment to standard therapy may alleviate pain associated with a sickling crisis and potentially reduce the severity and duration of a crisis. This may shorten the time in hospital and potentially improve the quality of life for patients with sickle cell anemia.

Conditions

Anemia, Sickle Cell; Sickle Cell Anemia; Sickle Cell Disease; Sickle Cell Disorders; Hemoglobin SC Disease; Sickle Cell Hemoglobin C Disease

Keywords

Sickle cell anemia; Sickle cell disease; Sickling crisis; Vaso-occlusive crisis; Carboxyhemoglobin; Oxygen therapeutic; Ischemic rescue therapy; Hemoglobin solution; Pegylated hemoglobin

Outcome Measures

Primary Outcomes (1)

• Duration of hospitalization for treatment of painful vaso-occlusive crisis (VOC)

  Time from randomization to resolution of the vaso-occlusive crisis, assessed by evaluation of cessation of opioid analgesia, recovery of ambulation, and/or ready for hospital discharge.

  Up to 28 days

Secondary Outcomes (4)

• Pain levels

  Up to 7 days

• Readmission to emergency room (ER)

  Up to 28 days

• Re-admission to hospital for treatment of VOC

  Up to 28 days

• Acute Chest Syndrome (ACS) complications

  Up to 28 days

Other Outcomes (4)

• Adverse events

  Up to 28 days

• Urine biomarkers

  Up to 7 days

• Ambulation

  Daily up to 7 days

Study Arms (2)

MP4CO

EXPERIMENTAL

Escalating doses of MP4CO, administered intravenously

Drug: MP4CO

Sodium chloride solution

ACTIVE COMPARATOR

Normal saline (0.9% Sodium Chloride Injection USP)administered intravenously

Drug: Sodium chloride solution

Interventions

MP4CO DRUG

43 mg/mL pegylated carboxyhemoglobin \[≥ 90% CO hemoglobin saturation\] in physiological acetate electrolyte solution

Also known as: Pegylated carboxyhemoglobin, PEG carboxyhemoglobin

MP4CO

Sodium chloride solution DRUG

Normal saline solution (0.9% Sodium Chloride Injection USP)

Also known as: Normal saline, Sodium chloride USP, 0.9% NaCl solution

Sodium chloride solution

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Informed Consent (and assent as required for minors)
• Diagnosis of SCD (known HbSS or HbSß0)
• Sixteen years of age or older
• Prior history of at least one VOC requiring hospitalization within the last 24 months

You may not qualify if:

• ≥ 5 VOCs within the preceding 6 months requiring Emergency Room (ER) visits or hospital admissions
• History of overt stroke or cerebral vascular accident within the previous 12 months
• Remained in the hospital for ≥2 weeks (14 days) for VOC management within the previous 6 months
• Known pulmonary hypertension based on an estimated tricuspid regurgitant jet velocity (TRJV) \>2.90 m/s or definitive diagnosis by prior right heart catheterization
• Baseline SaO2 level by pulse oximetry \<92% on room air
• Systemic hypertension (baseline systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 90 mmHg)
• History of myocardial infarction, myocardial ischemia, or angina
• On a chronic red blood cell transfusion therapy program (simple or exchange)
• Renal dysfunction presenting with a GFR\<60 mL/min/1.73m
• Any diagnosis of a concurrent chronic debilitating disease that may affect the completion of the study or results of the study as determined by the investigator
• Currently enrolled in any other investigational treatment study
• Significant substance abuse.
• Known to have HIV, active hepatitis B, or C infection, or active tuberculosis

Sponsors & Collaborators

• Sangart: lead

Study Sites (14)

Salmaniya Medical Complex

Manama, Bahrain

Location

University Hospital Brugmann

Brussels, Belgium

Location

Rio de Janerio Instituto Estadual de Hematologie

Rio de Janerio, Brazil

Location

Hôpital Henri Mondor

Créteil, France

Location

Georges Pompidou European University Hospital

Paris, France

Location

American Univ. of Beirut Medical Center

Beirut, Lebanon

Location

Univ. Medical Center Rizk Hospital

Beirut, Lebanon

Location

Academic Medical Center

Amsterdam, Netherlands

Location

Cornell Medical City

Doha, Qatar

Location

Cukurova University Medical Facilty

Adana, Turkey (Türkiye)

Location

Mersin University Medical Faculty

Mersin, Turkey (Türkiye)

Location

Guys Hospital

London, United Kingdom

Location

King's College Hospital

London, United Kingdom

Location

Queen Mary Hospital

London, United Kingdom

Location

Related Publications (14)

• Vandegriff KD, Young MA, Lohman J, Bellelli A, Samaja M, Malavalli A, Winslow RM. CO-MP4, a polyethylene glycol-conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats. Br J Pharmacol. 2008 Aug;154(8):1649-61. doi: 10.1038/bjp.2008.219. Epub 2008 Jun 9.

  PMID: 18536756 BACKGROUND

• Vandegriff KD, Bellelli A, Samaja M, Malavalli A, Brunori M, Winslow RM. Kinetics of NO and O2 binding to a maleimide poly(ethylene glycol)-conjugated human haemoglobin. Biochem J. 2004 Aug 15;382(Pt 1):183-9. doi: 10.1042/BJ20040156.

  PMID: 15175010 BACKGROUND

• Tsai AG, Vandegriff KD, Intaglietta M, Winslow RM. Targeted O2 delivery by low-P50 hemoglobin: a new basis for O2 therapeutics. Am J Physiol Heart Circ Physiol. 2003 Oct;285(4):H1411-9. doi: 10.1152/ajpheart.00307.2003. Epub 2003 Jun 12.

  PMID: 12805024 BACKGROUND

• Cole RH, Vandegriff KD. MP4, a vasodilatory PEGylated hemoglobin. Adv Exp Med Biol. 2011;701:85-90. doi: 10.1007/978-1-4419-7756-4_12.

  PMID: 21445773 BACKGROUND

• Vandegriff KD, Malavalli A, Mkrtchyan GM, Spann SN, Baker DA, Winslow RM. Sites of modification of hemospan, a poly(ethylene glycol)-modified human hemoglobin for use as an oxygen therapeutic. Bioconjug Chem. 2008 Nov 19;19(11):2163-70. doi: 10.1021/bc8002666.

  PMID: 18837531 BACKGROUND

• Svergun DI, Ekstrom F, Vandegriff KD, Malavalli A, Baker DA, Nilsson C, Winslow RM. Solution structure of poly(ethylene) glycol-conjugated hemoglobin revealed by small-angle X-ray scattering: implications for a new oxygen therapeutic. Biophys J. 2008 Jan 1;94(1):173-81. doi: 10.1529/biophysj.107.114314. Epub 2007 Sep 7.

  PMID: 17827244 BACKGROUND

• Tsai AG, Cabrales P, Manjula BN, Acharya SA, Winslow RM, Intaglietta M. Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell-free hemoglobin oxygen carriers. Blood. 2006 Nov 15;108(10):3603-10. doi: 10.1182/blood-2006-02-005272. Epub 2006 Jul 20.

  PMID: 16857991 BACKGROUND

• Vandegriff KD, McCarthy M, Rohlfs RJ, Winslow RM. Colloid osmotic properties of modified hemoglobins: chemically cross-linked versus polyethylene glycol surface-conjugated. Biophys Chem. 1997 Nov;69(1):23-30. doi: 10.1016/s0301-4622(97)00079-3.

  PMID: 9440206 BACKGROUND

• Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012 Nov 1;120(18):3647-56. doi: 10.1182/blood-2012-04-383430. Epub 2012 Aug 24.

  PMID: 22923496 BACKGROUND

• Belcher JD, Young M, Chen C, Nguyen J, Burhop K, Tran P, Vercellotti GM. MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice. Blood. 2013 Oct 10;122(15):2757-64. doi: 10.1182/blood-2013-02-486282. Epub 2013 Aug 1.

  PMID: 23908468 BACKGROUND

• Belcher JD, Mahaseth H, Welch TE, Otterbein LE, Hebbel RP, Vercellotti GM. Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. J Clin Invest. 2006 Mar;116(3):808-16. doi: 10.1172/JCI26857. Epub 2006 Feb 16.

  PMID: 16485041 BACKGROUND

• Bilban M, Haschemi A, Wegiel B, Chin BY, Wagner O, Otterbein LE. Heme oxygenase and carbon monoxide initiate homeostatic signaling. J Mol Med (Berl). 2008 Mar;86(3):267-79. doi: 10.1007/s00109-007-0276-0. Epub 2007 Nov 22.

  PMID: 18034222 BACKGROUND

• Piantadosi CA, Withers CM, Bartz RR, MacGarvey NC, Fu P, Sweeney TE, Welty-Wolf KE, Suliman HB. Heme oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression. J Biol Chem. 2011 May 6;286(18):16374-85. doi: 10.1074/jbc.M110.207738. Epub 2011 Mar 18.

  PMID: 21454555 BACKGROUND

• Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Medicine (Baltimore). 2005 Nov;84(6):363-376. doi: 10.1097/01.md.0000189089.45003.52.

  PMID: 16267411 BACKGROUND

Related Links

• Sangart, Inc. (Sponsor home page)

MeSH Terms

Conditions

Anemia, Sickle Cell; Hemoglobin SC Disease; Vaso-Occlusive Crises

Interventions

PEGylated carboxyhemoglobin bovine; Sodium Chloride; Saline Solution

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Tania Small, MD

  Sangart, Inc., San Diego, CA

  STUDY DIRECTOR

• Swee Lay Thein, MD

  King's College Hospital NHS Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 14, 2013
• First Posted: August 19, 2013
• Study Start: October 1, 2013
• Primary Completion: June 1, 2015
• Study Completion: October 1, 2015
• Last Updated: October 28, 2013

Record last verified: 2013-10

Locations

BE (1); FR (2); NL (1); BA (1); GB (3); BR (1); QA (1); TU (2); LE (2)